Pancreatic cancer is the fourth leading cause of cancer-related death in the USA and Europe; early symptoms and screenings are lacking, and it is usually diagnosed late with a poor prognosis. Circulating tumor cells (CTCs) have been promising new biomarkers in solid tumors. In the last twenty years (1999–2019), 140 articles have contained the key words “Circulating tumor cells, pancreatic cancer, prognosis and diagnosis.” Articles were evaluated for the use of CTCs as prognostic markers and their correlation to survival in pancreatic ductal adenocarcinoma (PDAC). In the final selected 17 articles, the CTC detection rate varied greatly between different enrichment methodologies and ranged from 11% to 92%; the majority of studies used the antigen-dependent CellSearch^© system for CTC detection. Fifteen of the reviewed studies showed a correlation between CTC presence and a worse overall survival. The heterogeneity of CTC-detection methods and the lack of uniform results hinder a comparison of the evaluated studies. However, CTCs can be detected in pancreatic cancer and harbor a hope to serve as an early detection tool. Larger studies are needed to corroborate CTCs as valid biomarkers in pancreatic cancer.

Background: Pancreatic acinar cell carcinoma (PACC) is a distinct type of pancreatic cancer with low prevalence. We aimed to analyze prognostic factors and survival outcome for PACC in comparison to pancreatic ductal adenocarcinoma (PDAC), based on data from the German Cancer Registry Group. Methods: Patients with PACC and PDAC were extracted from pooled data of the German clinical cancer registries (years 2000 to 2019). The distribution of demographic parameters, tumor stage and therapy modes were compared between PACC and PDAC. The Kaplan–Meier method and Cox regression analysis were used to delineate prognostic factors for PACC. Propensity score matching was used to compare survival between PACC and PDAC. Results: There were 233 (0.44%) patients with PACC out of 52,518 patients with pancreatic malignancy. Compared to PDAC, patients with PACC were younger (median age 66 versus 70, respectively, p < 0.001) and the percentage of males was higher (66.1% versus 53.3%, respectively, p < 0.001). More patients were resected with PACC than with PDAC (56.2% versus 38.9%, respectively, p < 0.001). The estimated overall median survival in PACC was 22 months (95% confidence interval 15 to 27), compared to 12 months (95% confidence interval 10 to 13) in the matched PDAC cohort (p < 0.001). Surgical resection was the strongest positive prognostic factor for PACC after adjusting for sex, age, and distant metastases (hazard ratio 0.34, 95% confidence interval 0.22 to 0.51, p < 0.001). There was no survival benefit for adjuvant therapy in PACC. Conclusions: PACC has overall better prognosis than PDAC. Surgical resection is the best therapeutic strategy for PACC and should be advocated even in advanced tumor stages.

Formalin-fixed, paraffin-embedded (FFPE) tissues represent the most abundant resource of archived human specimens in pathology. Such tissue specimens are emerging as a highly valuable resource for translational proteomic studies. In quantitative proteomic analysis, reductive di-methylation of primary amines using stable isotopic formaldehyde variants is increasingly used due to its robustness and cost-effectiveness. In the present study we show for the first time that isotopic amine dimethylation can be used in a straightforward manner for the quantitative proteomic analysis of FFPE specimens without interference from formalin employed in the FFPE process. Isotopic amine dimethylation of FFPE specimens showed equal labeling efficiency as for cryopreserved specimens. For both FFPE and cryopreserved specimens, differential labeling of identical samples yielded highly similar ratio distributions within the expected range for dimethyl labeling. In an initial application, we profiled proteome changes in clear cell renal cell carcinoma (ccRCC) FFPE tissue specimens compared to adjacent non–malignant renal tissue. Our findings highlight increased levels of glyocolytic enzymes, annexins as well as ribosomal and proteasomal proteins. Our study establishes isotopic amine dimethylation as a versatile tool for quantitative proteomic analysis of FFPE specimens and underlines proteome alterations in ccRCC.

Background: To evaluate recurrence in patients with post-neoadjuvant pathological complete response (pCR) and in patients with complete response of primary tumor but persisting lymphatic spread of disease (non-pCR, ypT0ypN +) of esophageal cancer. Methods: Seventy-five patients (63 pCR, 12 non-pCR) were analyzed retrospectively. Pattern and incidence of local and distant recurrence as well as the impact on overall (OS) and disease-free survival (DFS) were evaluated. The efficacy of neoadjuvant chemotherapy according to FLOT protocol was compared to neoadjuvant chemoradiation according to CROSS protocol. Results: In the pCR group, isolated local recurrence was diagnosed in 3%, while no isolated local recurrence was observed in the non-pCR group due to the high incidence of distant recurrence. Distant recurrence was most common in both cohorts (isolated distant recurrence: pCR group 10% to non-pCR group 55%; simultaneous distant and local recurrence: pCR group 3% to non-pCR group 18%). Median time to distant recurrence was 5.5 months, and median time to local recurrence was 8.0 months. Cumulative incidence of distant recurrence (with and without simultaneous local recurrence) was 16% (± 6%) in pCR patients and 79% (± 13%) in non-pCR patients (hazard ratio (HR) 0.123) estimated by Kaplan–Meier method. OS (HR 0.231) and DFS (HR 0.226) were significantly improved in patients with pCR compared to patients with non-pCR. Advantages for FLOT protocol compared to CROSS protocol, especially with regard to distant control of disease (HR 0.278), were observed (OS (HR 0.361), DFS (HR 0.226)). Conclusion: Distant recurrence is the predominant site of treatment failure in patients with pCR and non-pCR grade 1a regression, whereby recurrence rates are much higher in patients with non-pCR.

Intraductal papillary mucinous neoplasm (IPMN) is the most common pancreatic cyst and a precursor of pancreatic cancer (PDAC). Since PDAC has a devastatingly high mortality rate, the early diagnosis and treatment of any precursor lesion are rational. The safety of the existing guidelines on the clinical management of IPMN has been criticized due to unsatisfactory sensitivity and specificity, showing the need for further markers. Blood obtained from patients with IPMN was therefore subjected to size-based isolation of circulating epithelial cells (CECs). We isolated CECs and evaluated their cytological characteristics. Additionally, we compared Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations in CECs and the primary IPMN tissue, since KRAS mutations are very typical for PDAC. Samples from 27 IPMN patients were analyzed. In 10 (37%) patients, CECs were isolated and showed a hybrid pattern of surface markers involving both epithelial and mesenchymal markers, suggesting a possible EMT process of the cells. Especially, patients with high-grade dysplasia in the main specimen were all CEC-positive. KRAS mutations were also present in CECs but less common than in IPMN tissue. The existence of CEC in IPMN patients offers additional blood-based research possibilities for IMPN biology.

Background: Cathepsin L (Ctsl) is a cysteine protease mainly located within the endosomal/lysosomal cell compartment. High expression of Ctsl indicates poor prognosis in human breast cancer. However, the cell type-specific Ctsl functions responsible for this association remain elusive. Methods: Because constitutive Ctsl^−/− mice develop a complex phenotype, we developed a conditional model allowing for cell type-specific inactivation of Ctsl in mammary epithelium or myeloid cells in the transgenic mouse mammary tumor virus (MMTV)-polyoma middle T (PyMT) breast cancer model. Results: Ctsl ablation in mammary epithelial cells resulted in delayed initiation and end-stage of cancers. The latter displayed large dead cell areas. Inducible in vitro deletion of Ctsl in MMTV-PyMT-derived breast cancer cells revealed expansion of the acidic cell compartment, alteration of intracellular amino acid levels, and impaired mTOR signaling. In consequence, Ctsl-deficient cells exhibited slow growth rates and high apoptosis susceptibility. In contrast to Ctsl-deficient mammary epithelium, selective knockout of Ctsl in myeloid cells had no effects on primary tumors, but promoted lung metastasis formation. Conclusions: Our cell type-specific in vivo analysis provides strong evidence for a cancer cell-intrinsic, tumor-promoting role of Ctsl in primary breast cancer, whereas metastasis is negatively regulated by Ctsl expressed by bone marrow-derived cells.